The search for drugs to alleviate Usher’s Syndrome III, a rare disease that leaves its victims blind and deaf

Drug discovery may sound like a search for the proverbial needle in a haystack.

But that’s really just the beginning. Once you identify a promising compound from a cast of thousands, you need to modify it and fine-tune it until it can affect the desired target. And then, ideally, you want to know what that target is.

Recent work our lab did on Usher’s Syndrome III—part of a cluster of disorders that leaves victims both blind and deaf—shows how academia, industry and disease foundations (in this case the Usher III Initiative) worked together in this needle-in-a-haystack environment to find a promising new small molecule that might be able to prevent the symptoms of Usher’s III.

[Our work on Usher’s III was featured at the World Preclinical Congress in Boston June 12-17]

Usher’s syndrome was named after a Scottish ophthalmologist who examined the pathology and transmission in the early 1900s. Three subtypes are known, which are divided by the degree of hearing and vision loss, the age when deafness loss occurs and how quickly it progresses. We now know that these three subtypes have differing genetic causes. Unfortunately, there is no cure for Usher’s and no effective therapies.

Usher’s Syndrome III is caused by a mutation of a single gene, the clarin-1 gene, which was reported from independent labs in 2001 and 2002. This gene encodes for the protein clarin-1 whose exact function is not known, though evidence suggests it is involved in development and maintenance of structures within the inner ear and retina.

Even though Usher’s III has the lowest incidence, it has the greatest therapeutic potential for treatment due to the later onset and slower progression of hearing and vision loss. And since it is caused by a single mutation it should, theoretically, be easier to identify a single therapeutic agent compared to multiple sclerosis, Parkinson’s disease and other multifactorial diseases.

To find solutions for Usher’s III, you first need to locate those “needles” that might be able to restore the clarin1 protein function. And because we are talking about a neurological condition, there is the added difficulty of finding drugs that can be ushered across the blood-brain barrier.

But how to find a “needle” without a target to aim at? To do this Case Western Reserve University developed an assay to detect the clarin-1 in cells which were genetically engineered to produce the mutant protein. If a compound could rescue the protein then it could be detected with a fluorescent antibody.

With a method in place we needed a haystack to search and we used a large one indeed, 50,000 compounds from the University of Cincinnati.

Even so at the end of the process only one compound remained, our team of medicinal chemists in the UK then got to work to produce new molecules based on this one hit that would have improved potency and the other physical properties that could provide a drug

Because Usher’s causes people to go blind and deaf, drugs need to reach the regions of the body that allow us to hear and see. That means compounds must be able to pass through the highly selective membrane barrier that separates the eyes and ears from the bloodstream.

For instance, the membrane proteins in small-molecule drugs need to be of a certain “greasiness” to penetrate these barriers. Too greasy and they stick to the cell membrane and fail to pass through. However if they are too polar they can be recognized by transporter proteins in the membrane that usher them back out. We used an MDCK assay that uses a layer of engineered cells to mimic this barrier and allow us to assess the potential for each compound to reach the site of action.

Whilst chemists were working on finding the right molecule Case Western scientists were working to produce a disease relevant animal model in which to test the compound

The winning compound was ultimately tested in a mouse model developed to mimic the progressive hearing loss associated with Usher’s III clarin-1 N48K gene mutation. The young mice treated with the compound—BF844—had 1,000 to 10,000 more sensitive hearing than the untreated mice, which was reported last year in Nature Chemical Biology.

So what happens next? The Usher III Initiative, which funded the work and owns the intellectual property for these compounds, is interested in finding a willing pharmaceutical company to take this small molecule project to the next level and develop it for the clinic.

Hopefully, this collaborative search for solutions to Usher’s will lead to successful therapies for the children and families victimized by this disease. Stay tuned.

For more information about Usher III visit the Usher III initiative at http://usheriii.org/.